The mammalian fatty acid amides (FAAs) have been directly linked to the regulation of pain thresholds, body temperature, sleep cycles, appetite, and higher-level cognitive processes such as memory and learning. Nonetheless, how FAAs influence nervous system function is poorly understood. While some of these molecules trigger the central cannabinoid receptor CB1, other members of this class lack described molecular targets. The enzyme fatty acid amide hydrolase (FAAH) controls the levels of fatty acid amides in vivo, setting the baseline function of their various corresponding physiologies. We have recently determined the three dimensional structure of this integral membrane protein, and we are now prepared to begin second-generation structure determination efforts to extend our knowledge of the mechanisms of action of this important enzyme. The studies described in this application (Project II of the Program Project) aim to determine higher resolution FAAH structures, as well as structures of human FAAH, apo-FAAH, FAAH-inhibitor/product complexes, and key FAAH mutants, including the natural P129T variant associated with problem drug use. Information accrued from our studies will not only enlighten our understanding of FAAH but will also serve as a guide for the development of agents designed to intersect the cannabinoid and other FAA systems in vivo, possibly to therapeutic benefit.